1. Field of the Invention
The present invention relates to a process for the preparation of etoposide phosphate and intermediates thereof.
2. Description of the Prior Art
Etoposide phosphate is a useful compound having an antitumor activity, which is improved in water-solubility as compared with etoposide. Processes for the preparation thereof have been reported in Japanese Patent Laid-Open No. 192793/1988 and U.S. Pat. No. 4,904,768.
The process disclosed in the U.S. Pat. No. 4,904,768 comprises reacting etoposide directly with phosphorus oxychloride or an alkyl or aryl chlorophosphate, and therefore gives a large amount of by-products by the reaction of such a phosphorus compound with the hydroxyl groups of the saccharide moiety in addition to the objective compound wherein the phosphorus compound is bonded to the 4'-position of etoposide. Accordingly, the reaction mixture obtained by the process must be subjected to specific treatment such as column chromatography to remove the by-products. On the other hand, the process disclosed in the Japanese Patent Laid-Open No. 192793/1988 uses etoposide wherein the hydroxyl groups of the saccharide moiety are blocked, and therefore gives little by-products. However, the process involves the use of acetic acid and zinc in the deblocking of the saccharide moiety and necessitates the isolation of the objective etoposide phosphate by lyophilization, thus being problematic in conducting mass-production.